TY - JOUR
T1 - Mitochondrial Complex 1, Sigma 1, and Synaptic Vesicle 2A in Early Drug-Naive Parkinson's Disease
AU - Wilson, Heather
AU - Pagano, Gennaro
AU - de Natale, Edoardo Rosario
AU - Mansur, Ayla
AU - Caminiti, Silvia Paola
AU - Polychronis, Sotirios
AU - Middleton, Lefkos T.
AU - Price, Geraint
AU - Schmidt, Karl F.
AU - Gunn, Roger N.
AU - Rabiner, Eugenii A.
AU - Politis, Marios
PY - 2020/8/1
Y1 - 2020/8/1
N2 - Background: Dysfunction of mitochondrial energy generation may contribute to neurodegeneration, leading to synaptic loss in Parkinson's disease (PD). The objective of this study was to find cross-sectional and longitudinal changes in PET markers of synaptic vesicle protein 2A, sigma 1 receptor, and mitochondrial complex 1 in drug-naive PD patients. Methods: Twelve early drug-naive PD patients and 16 healthy controls underwent a 3-Tesla MRI and PET imaging to quantify volume of distribution of [11C]UCB-J, [11C]SA-4503, and [18F]BCPP-EF for synaptic vesicle protein 2A, sigma 1 receptor, and mitochondrial complex 1, respectively. Nine PD patients completed approximately 1-year follow-up assessments. Results: Reduced [11C]UCB-J volume of distribution in the caudate, putamen, thalamus, brain stem, and dorsal raphe and across cortical regions was observed in drug-naive PD patients compared with healthy controls. [11C]UCB-J volume of distribution was reduced in the locus coeruleus and substantia nigra but did not reach statistical significance. No significant differences were found in [11C]SA-4503 and [18F]BCPP-EF volume of distribution in PD compared with healthy controls. Lower brain stem [11C]UCB-J volume of distribution correlated with Movement Disorder Society Unified Parkinson's Disease Rating Scale part III and total scores. No significant longitudinal changes were identified in PD patients at follow-up compared with baseline. Conclusions: Our findings represent the first in vivo evidence of mitochondrial, endoplasmic reticulum, and synaptic dysfunction in drug-naive PD patients. Synaptic dysfunction likely occurs early in disease pathophysiology and has relevance to symptomatology. Mitochondrial complex 1 and sigma 1 receptor pathology warrants further investigations in PD. Studies in larger cohorts with longer follow-up will determine the validity of these PET markers to track disease progression.
AB - Background: Dysfunction of mitochondrial energy generation may contribute to neurodegeneration, leading to synaptic loss in Parkinson's disease (PD). The objective of this study was to find cross-sectional and longitudinal changes in PET markers of synaptic vesicle protein 2A, sigma 1 receptor, and mitochondrial complex 1 in drug-naive PD patients. Methods: Twelve early drug-naive PD patients and 16 healthy controls underwent a 3-Tesla MRI and PET imaging to quantify volume of distribution of [11C]UCB-J, [11C]SA-4503, and [18F]BCPP-EF for synaptic vesicle protein 2A, sigma 1 receptor, and mitochondrial complex 1, respectively. Nine PD patients completed approximately 1-year follow-up assessments. Results: Reduced [11C]UCB-J volume of distribution in the caudate, putamen, thalamus, brain stem, and dorsal raphe and across cortical regions was observed in drug-naive PD patients compared with healthy controls. [11C]UCB-J volume of distribution was reduced in the locus coeruleus and substantia nigra but did not reach statistical significance. No significant differences were found in [11C]SA-4503 and [18F]BCPP-EF volume of distribution in PD compared with healthy controls. Lower brain stem [11C]UCB-J volume of distribution correlated with Movement Disorder Society Unified Parkinson's Disease Rating Scale part III and total scores. No significant longitudinal changes were identified in PD patients at follow-up compared with baseline. Conclusions: Our findings represent the first in vivo evidence of mitochondrial, endoplasmic reticulum, and synaptic dysfunction in drug-naive PD patients. Synaptic dysfunction likely occurs early in disease pathophysiology and has relevance to symptomatology. Mitochondrial complex 1 and sigma 1 receptor pathology warrants further investigations in PD. Studies in larger cohorts with longer follow-up will determine the validity of these PET markers to track disease progression.
KW - mitochondria
KW - molecular biomarkers
KW - Parkinson's disease
KW - positron emission tomography
KW - synaptic vesicle protein
UR - http://www.scopus.com/inward/record.url?scp=85084008918&partnerID=8YFLogxK
U2 - 10.1002/mds.28064
DO - 10.1002/mds.28064
M3 - Article
AN - SCOPUS:85084008918
SN - 0885-3185
VL - 35
SP - 1416
EP - 1427
JO - Movement disorders : official journal of the Movement Disorder Society
JF - Movement disorders : official journal of the Movement Disorder Society
IS - 8
ER -